Animal models have been used to study accelerated aging, accelerated senescence, premature aging, premature senescence, and progeria-like syndromes. These models may be grouped into four general classes: (1) experimentally induced models, (2) gene-modified models, (3) selection models, and (4) spontaneous models. There has been much debate over the connection between accelerated aging and disease status in animal models. Investigators interested in the basic mechanisms of normal aging have had to be prudent in their choice of animal models because early diseases leading to reduced life spans usually result from certain defects unrelated to mechanisms associated with normal aging.
Age-related diseases (or symptoms) are complications that generally arise from senescence. Non-limiting examples of age-related diseases (or symptoms) are, for example, cardiovascular disease, heart dysfunction, auditory function loss, anemia, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, neurodegeneration (e.g., Alzheimer's disease (AD), and the like), increased presence of apoptotic markers, loss of bone mass, etc. Generally, the incidence of these age-related diseases (or symptoms) increases rapidly with aging (e.g., increases exponentially with age, in the case of cancer).
An animal model for accelerated aging has been described in the art. The senescence-accelerated-prone mouse strain 8 (SAMP8) [55, 176-180] have shorter median life spans of 10-12 months, approximate 40 to 50% of that of other laboratory mouse strains, such as C57/B6. This animal model for accelerated aging also exhibits age-related symptoms, such as accelerated deterioration of learning and memory, with immunoreactive AB-containing granules, Tau hyperphosphorylation, and other features such as neuronal cell loss, which are characteristic of Alzheimer's disease pathogenesis. SAMP8 may also show premature old age condition, i.e., loss of hair, hair coat not smooth with yellowish tint, and significant decrease of mobility and food intake. However, the molecular basis for the SAMP8 age-related symptoms remains unclear. The use of these animal models for selecting candidate compounds for treating, delaying or preventing accelerated aging and/or an age-associated symptom, such as AD, remains unsatisfactory.
Animal models for age-related diseases (or symptoms) have also been described in the art. The transgenic APPswe mouse [172], an animal model for AD, carries a transgene capable of expressing the human β-amyloid (Aβ) precursor polypeptide swe mutant and produces amyloid plaques in the animal brain. The transgenic Tau-mutant mouse [173], an animal model for AD, carries a transgene capable of expressing the Tau P301 mutant and produces neurofibrillary tangles. The double transgenic APPswe+Tau mouse [174], an animal model for AD, carries a transgene capable of expressing both mutants. AD patients are generally classified in two broad categories: “sporadic” AD cases and “early-onset” AD cases. Victims that manifest AD symptoms at ages above 65, with increasing risk through the 70's and 80's, are classified as sporadic AD cases. Sporadic AD cases represent about 95% of total AD victim population, and are believed to not be genetically inherited, although some genes may act as risk factors. Victims that manifest AD symptoms at ages younger than 65 are classified as early-onset AD cases. Early-onset AD cases represent about 5% of total AD victim population, and may have a familial history of this disease. The AD familial cases, some 1% of the total AD victim population, exhibit genetic mutations for amyloid precursor polypeptide on chromosome 21, for Presenilin 1 polypeptide on chromosome 14, and/or for Presenilin 2 polypeptide on chromosome 1. Most of the transgenic animal strains developed as animal models for AD are thus based on gene mutations discovered in early-onset familial AD. Early-onset familial AD models are currently used in drug efficacy tests and vaccine development [Cruts M, Van Broeckhoven C. (1998) Ann Med 30: 560-565; Ruis J. (2008) Rev. Infirm. 143: 14-15; Hsiao K, et al. (1996) Science 274:99-102]. However, the use of these animal models for selecting candidate compounds for treating, delaying or preventing accelerated aging and/or an age-associated symptom, such as sporadic AD, remains unsatisfactory.